Development of molecular targeted therapy for thyroid cancer using tyrosine kinase inhibition with a novel mechanism of action

• Project/Area Number: 15K10076
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Chubu University
• Principal Investigator: Takeda Kozue 中部大学, 生命健康科学部, 准教授 (80345884)
• Co-Investigator(Kenkyū-buntansha): 川本 善之 中部大学, 生命健康科学部, 准教授 (10410664)
• Project Period (FY): 2015-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: がん / RET / チロシンキナーゼ / 阻害

Outline of Final Research Achievements

Identification of RET kinase inhibitors promises valuable therapeutic tools for the intervention of RET-driven tumors. We have previously reported that a conserved cysteine of RET is crucial to the disulfide-bonded dimerization-linked activation of RET kinases. Reagents which bind to this cysteine may inhibit the activity of RET kinases through disulfide-bond mediated dimerization. We examine the potential of cysteine containing peptides as candidate kinase inhibitors. We demonstrate that these peptides inhibit the activities of RET and its downstream kinases and effectively reducing the malignant potential of RET-expressing cells. These peptides were also found to be effective against the drug resistant mutant of RET. The inhibition of RET kinase activity by these peptides resulted in suppression of RET-mediated cancer cell growth.

Academic Significance and Societal Importance of the Research Achievements

RETキナーゼが関与するがんに対する新規分子標的療法の候補分子を探索し、その効果を細胞レベルから実験動物レベルで検討を行った。
これまでのチロシンキナーゼ阻害剤と全く異なった、システインを介する二量体化という新しい活性化機序に基づく新規阻害剤の開発は、我々独自のものである。がんの治療において一種類の薬剤が全ての患者に有効であることはほとんどない。全く作用機序の異なった薬剤は、これまでの薬剤が無効な場合、あるいは耐性化した場合に非常に重要であり、本研究がさらに進めば、治療法の選択肢を増やすことに貢献できる。

Research Products

• [Journal Article] Peptides containing the MXXCW motif inhibit oncogenic RET kinase activity with a novel mechanism of action. (2020)
  • Author(s): Takeda K, Kawamoto Y, Nagasaki Y, Okuno Y, Goto Y, Iida M, Yajima I, Ohgami N, Kato M.
  • Journal Title: Am J Cancer Res. Volume: 10 Pages: 336-349
  • Peer Reviewed / Open Access
• [Presentation] システインを介したRETキナーゼの活性阻害 (2019)
  • Author(s): 武田湖州恵、川本善之、坂川久仁子、川添健司、矢嶋伊知朗、大神信孝、加藤昌志
  • Organizer: 第89回日本衛生学会学術総会